* Professor, Department of Anesthesia, Stanford University School of Medicine, Stanford, California, and Anesthesiologist and Intensivist, Palo Alto VA Health Care System, Palo Alto, California. † Doctoral Candidate, ‡ Professor of Computational Structural Biology, Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden; Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden. § Professor of Chemistry in Anesthesia, Department of Anesthesia, Stanford University School of Medicine.
Anesthesiology. 2013 Nov;119(5):1087-95. doi: 10.1097/ALN.0b013e31829e47e3.
Anesthetics mediate portions of their activity via modulation of the γ-aminobutyric acid receptor (GABAaR). Although its molecular structure remains unknown, significant progress has been made toward understanding its interactions with anesthetics via molecular modeling.
The structure of the torpedo acetylcholine receptor (nAChRα), the structures of the α4 and β2 subunits of the human nAChR, the structures of the eukaryotic glutamate-gated chloride channel (GluCl), and the prokaryotic pH-sensing channels, from Gloeobacter violaceus and Erwinia chrysanthemi, were aligned with the SAlign and 3DMA algorithms. A multiple sequence alignment from these structures and those of the GABAaR was performed with ClustalW. The Modeler and Rosetta algorithms independently created three-dimensional constructs of the GABAaR from the GluCl template. The CDocker algorithm docked a congeneric series of propofol derivatives into the binding pocket and scored calculated binding affinities for correlation with known GABAaR potentiation EC50s.
Multiple structure alignments of templates revealed a clear consensus of residue locations relevant to anesthetic effects except for torpedo nAChR. Within the GABAaR models generated from GluCl, the residues notable for modulating anesthetic action within transmembrane segments 1, 2, and 3 converged on the intersubunit interface between α and β subunits. Docking scores of a propofol derivative series into this binding site showed strong linear correlation with GABAaR potentiation EC50.
Consensus structural alignment based on homologous templates revealed an intersubunit anesthetic binding cavity within the transmembrane domain of the GABAaR, which showed a correlation of ligand docking scores with experimentally measured GABAaR potentiation.
麻醉剂通过调节γ-氨基丁酸受体（GABAaR）发挥其部分作用。尽管其分子结构仍不清楚，但通过分子建模，人们对其与麻醉剂的相互作用有了重大的理解进展。
使用 SAlign 和 3DMA 算法对齐了来自于黄杆菌属（Gloeobacter violaceus）和菊欧文氏菌（Erwinia chrysanthemi）的 pH 感应通道和真核谷氨酸门控氯离子通道（GluCl）的结构与河豚乙酰胆碱受体（nAChRα）、人 nAChR 的α4 和β2 亚基的结构。使用 ClustalW 对这些结构和 GABAaR 的结构进行了多序列比对。Modeler 和 Rosetta 算法独立地使用 GluCl 模板创建了 GABAaR 的三维结构。CDocker 算法将一系列同源的丙泊酚衍生物对接入结合口袋，并对计算的结合亲和力进行评分，以与已知的 GABAaR 增强的 EC50 值进行相关性分析。
模板的多重结构比对显示，除了河豚 nAChR 之外，与麻醉效果相关的残基位置有明显的共识。在从 GluCl 生成的 GABAaR 模型中，在跨膜区域 1、2 和 3 中调节麻醉作用的残基集中在α和β亚基之间的亚基界面上。该结合位点中一系列丙泊酚衍生物的对接评分与 GABAaR 增强的 EC50 呈强烈的线性相关。
基于同源模板的共识结构比对揭示了 GABAaR 跨膜域内的亚基间麻醉结合腔，其配体对接评分与实验测量的 GABAaR 增强呈相关性。
